Polycyclic pyrimidines as potassium ion channel modulators

ABSTRACT

The present invention provides a genus of polycyclic pyrimidines that are useful as modulators of potassium ion channels. The modulators of the invention are of use in both therapeutic and diagnostic methods.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/561,990, filed Apr. 13, 2004, which is incorporatedherein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

Ion channels are cellular proteins that regulate the flow of ions,including calcium, potassium, sodium and chloride into and out of cells.These channels are present in all human cells and affect suchphysiological processes as nerve transmission, muscle contraction,cellular secretion, regulation of heartbeat, dilation of arteries,release of insulin, and regulation of renal electrolyte transport. Amongthe ion channels, potassium ion channels are the most ubiquitous anddiverse, being found in a variety of animal cells such as nervous,muscular, glandular, immune, reproductive, and epithelial tissue. Thesechannels allow the flow of potassium in and/or out of the cell undercertain conditions. For example, the outward flow of potassium ions uponopening of these channels makes the interior of the cell more negative,counteracting depolarizing voltages applied to the cell. These channelsare regulated, e.g., by calcium sensitivity, voltage-gating, secondmessengers, extracellular ligands, and ATP-sensitivity.

Potassium ion channels are typically formed by four alpha subunits, andcan be homomeric (made of identical alpha subunits) or heteromeric (madeof two or more distinct types of alpha subunits). In addition, certainpotassium ion channels (those made from Kv, KQT and Slo or BK subunits)have often been found to contain additional, structurally distinctauxiliary, or beta subunits. These subunits do not form potassium ionchannels themselves, but instead they act as auxiliary subunits tomodify the functional properties of channels formed by alpha subunits.For example, the Kv beta subunits are cytoplasmic and are known toincrease the surface expression of Kv channels and/or modifyinactivation kinetics of the channel (Heinemann et al., J. Physiol. 493:625-633 (1996); Shi et al., Neuron 16(4): 843-852 (1996)). In anotherexample, the KQT family beta subunit, minK, primarily changes activationkinetics (Sanguinetti et al., Nature 384: 80-83 (1996)).

The alpha subunits of potassium ion channels fall into at least 8families, based on predicted structural and functional similarities (Weiet al., Neuropharmacology 35(7): 805-829 (1997)). Three of thesefamilies (Kv, eag-related, and KQT) share a common motif of sixtransmembrane domains and are primarily gated by voltage. Two otherfamilies, CNG and SK/IK, also contain this motif but are gated by cyclicnucleotides and calcium, respectively. Small (SK) and intermediate (IK)conductance calcium-activated potassium ion channels possess unitconductances of 2-20 and 20-85 pS, respectively, and are more sensitiveto calcium than are BK channels discussed below. For a review ofcalcium-activated potassium channels see Latorre et al., Ann. Rev. Phys.51: 385-399 (1989).

Three other families of potassium channel alpha subunits have distinctpatterns of transmembrane domains. Slo or BK family potassium channelshave seven transmembrane domains (Meera et al., Proc. Natl. Acad. Sci.U.S.A. 94(25): 14066-14071 (1997)) and are gated by both voltage andcalcium or pH (Schreiber et al., J. Biol. Chem. 273: 3509-3516 (1998)).Slo or BK potassium ion channels are large conductance potassium ionchannels found in a wide variety of tissues, both in the central nervoussystem and periphery. These channels are gated by the concerted actionsof internal calcium ions and membrane potential, and have a unitconductance between 100 and 220 pS. They play a key role in theregulation of processes such as neuronal integration, muscularcontraction and hormone secretion. They may also be involved inprocesses such as lymphocyte differentiation and cell proliferation,spermatocyte differentiation and sperm motility. Members of the BK(Atkinson et al., Science 253: 551-555 (1991); Adelman et al., Neuron 9:209-216 (1992); Butler, Science 261: 221-224 (1993)) subfamily have beencloned and expressed in heterologous cell types where they recapitulatethe fundamental properties of their native counterparts. Finally, theinward rectifier potassium channels (Kir), belong to a structural familycontaining two transmembrane domains, and an eighth functionally diversefamily (TP, or “two-pore”) contains two tandem repeats of this inwardrectifier motif.

Each type of potassium ion channel shows a distinct pharmacologicalprofile. These classes are widely expressed, and their activityhyperpolarizes the membrane potential. Potassium ion channels have beenassociated with a number of physiological processes, includingregulation of heartbeat, dilation of arteries, release of insulin,excitability of nerve cells, and regulation of renal electrolytetransport. Moreover, studies have indicated that potassium ion channelsare a therapeutic target in the treatment of a number of diseasesincluding central or peripheral nervous system disorders (e.g.,migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminalneuralgia, spasticity, mood disorders, brain tumors, psychoticdisorders, myokymia, seizures, epilepsy, hearing and vision loss,psychosis, anxiety, depression, dementia, memory and attention deficits,Alzheimer's disease, age-related memory loss, learning deficiencies,anxiety, traumatic brain injury, dysmenorrhea, narcolepsy and motorneuron diseases), as well as targets for neuroprotective agents (e.g.,to prevent stroke and the like); as well as disease states such asgastroesophogeal reflux disorder and gastrointestinal hypomotilitydisorders, irritable bowel syndrome, secretory diarrhea, asthma, cysticfibrosis, chronic obstructive pulmonary disease and rhinorrhea,convulsions, vascular spasms, coronary artery spasms, renal disorders,polycystic kidney disease, bladder spasms, urinary incontinence, bladderoutflow obstruction, ischemia, cerebral ischemia, ischemic heartdisease, angina pectoris, coronary heart disease, Reynaud's disease,intermittent claudication, Sjorgren's syndrome, arrhythmia,hypertension, myotonic muscle dystrophia, xerostomia, diabetes type II,hyperinsulinemia, premature labor, baldness, cancer, and immunesuppression.

Specifically, SK channels have been shown to have distinctpharmacological profiles. For example, using patch clamp techniques, theeffects of eight clinically relevant psychoactive compounds on SK2subtype channels were investigated (Dreixler et al., Eur. J. Pharmacol.401: 1-7 (2000)). The evaluated compounds are structurally related totricyclic antidepressants and include amitriptyline, carbamazepine,chlorpromazine, cyproheptadine, imipramine, tacrine and trifluperazine.Each of the compounds tested was found to block SK2 channel currentswith micromolar affinity. A number of neuromuscular inhibiting agentsexist that affect SK channels, e.g. apamin, atracurium, pancuronium andtubocurarine (Shah et al., Br J Pharmacol 129: 627-30 (2000)).

Moreover, patch clamp techniques have also been used to study the effectof the centrally acting muscle relaxant chlorzoxazone and threestructurally related compounds, 1-ethyl-2-benzimidazolinone (1-EBIO),zoxazolamine, and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one(NS 1619) on recombinant rat brain SK2 channels (rSK2 channels)expressed in HEK293 mammalian cells (Cao et al., J Pharmacol. Exp. Ther.296: 683-689 (2001)). When applied externally, chlorzoxazone, 1-EBIO,and zoxazolamine activated rSK2 channel currents in cells dialyzed witha nominally calcium-free intracellular solution.

The effects of metal cations on the activation of recombinant human SK4(also known as hIK1 or hKCa4) channels has also been studied (Cao andHouamed, FEBS Lett. 446: 137-41 (1999)). The ion channels were expressedin HEK 293 cells and tested using patch clamp recording. Of the ninemetals tested, cobalt, iron, magnesium, and zinc did not activate theSK4 channels when applied to the inside of SK4 channel-expressingmembrane patches. Barium, cadmium, calcium, lead, and strontiumactivated SK4 channels in a concentration-dependent manner. Calcium wasthe most potent metal, followed by lead, cadmium, strontium, and barium.

The SK channels are heteromeric complexes that comprise pore-forminga-subunits and the calcium binding protein calmodulin (CaM). CaM bindsto the SK channel through the CaM-binding domain (CaMBD), which islocated in an intracellular region of an α-subunit close to the pore.Based on a recently published crystal structure, calcium binding to theN-lobe of the CaM proteins on each of the four subunits initiates astructural change that allows a hydrophobic portion of the CaM proteinto interact with a CaMBD on an adjacent subunit. As each N-lobe on anadjacent subunit grabs the other CaMBD C-terminal region, a rotary forceis thought to be created between them which would drive open thechannel.

New classes of compounds that act to modulate the opening of potassiumion channels would represent a significant advance in the art andprovide the opportunity to develop treatment modalities for numerousdiseases associated with these channels. The present invention providesa new class of potassium ion channel modulators and methods of using themodulators.

BRIEF SUMMARY OF THE INVENTION

The present invention provides polycyclic pyrimidines, prodrugs,complexes, and pharmaceutically acceptable salts thereof, which areuseful in the treatment of diseases through the modulation of potassiumion flow through potassium ion channels.

In a first aspect, the potassium ion channel modulator is a compoundaccording to Formula I:

In Formula (I), A and B are independently substituted or unsubstituted5- or 6-membered heterocycloalkyl or substituted or unsubstituted 5- or6-membered heteroaryl. The symbol

The symbol

The symbol X is a bond, —CH₂—, or —NR⁴—. Y is a bond, —CH═N—NH—,—NH—CH₂—, or —NR⁵—.

The symbols s and t are independently integers from 1 to 4.

The symbol k is an integer from 1 to 2.

R¹, R², and R³ are independently H, —OH, —NH₂, —NO₂, —SO₂NH₂, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted 3- to 7-membered cycloalkyl,substituted or unsubstituted 5- to 7-membered heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or —NR⁷R⁸.

R⁷ and R⁸ are independently H, halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted 5- to 7-membered cycloalkyl, substituted or unsubstituted5- to 7-membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁷ and R⁸ are optionally joinedtogether with the nitrogen to which they are attached to form asubstituted or unsubstituted 5- to 7-membered heterocycloalkyl, orsubstituted or unsubstituted heteroaryl.

R⁴ and R⁵ are independently H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstituted3- to 7-membered cycloalkyl, substituted or unsubstituted 5- to7-membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Where a plurality of R¹, R², and/or R³ groups are present, each R¹, R²,and/or R³ is optionally different.

R¹, R², and R³ may optionally form part of a fused ring system.

In a second aspect, the present invention provides a method fordecreasing ion flow through potassium ion channels in a cell, comprisingcontacting the cell with a potassium ion channel modulating amount of amodulator of the present invention.

In a third aspect, the present invention provides a method for treatinga disease through the modulation of potassium ion flow through potassiumion channels. The modulators are useful in the treatment of central orperipheral nervous system disorders (e.g., migraine, ataxia, Parkinson'sdisease, bipolar disorders, trigeminal neuralgia, spasticity, mooddisorders, brain tumors, psychotic disorders, myokymia, seizures,epilepsy, hearing and vision loss, psychosis, anxiety, depression,dementia, memory and attention deficits, Alzheimer's disease,age-related memory loss, learning deficiencies, anxiety, traumatic braininjury, dysmenorrhea, narcolepsy and motor neuron diseases), and asneuroprotective agents (e.g., to prevent stroke and the like). Themodulators of the invention are also useful in treating disease statessuch as gastroesophogeal reflux disorder and gastrointestinalhypomotility disorders, irritable bowel syndrome, secretory diarrhea,asthma, cystic fibrosis, chronic obstructive pulmonary disease andrhinorrhea, convulsions, vascular spasms, coronary artery spasms, renaldisorders, polycystic kidney disease, bladder spasms, urinaryincontinence, bladder outflow obstruction, ischemia, cerebral ischemia,ischemic heart disease, angina pectoris, coronary heart disease,Reynaud's disease, intermittent claudication, Sjorgren's syndrome,arrhythmia, hypertension, myotonic muscle dystrophia, xerostomi,diabetes type II, hyperinsulinemia, premature labor, baldness, cancer,and immune suppression. This method involves administering, to apatient, an effective amount of a modulator of the present invention.

In a fourth aspect, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and amodulator of the present invention.

These and other aspects and embodiments of the invention will beapparent from the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION

I. Abbreviations and Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

Where moieties are specified by their conventional chemical formulae,written from left to right, they equally encompass the chemicallyidentical substituents that would result from writing the structure fromright to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀ or1- to 10-membered means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like. An unsaturated alkyl group is one having one or more doublebonds or triple bonds. Examples of unsaturated alkyl groups include, butare not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. The term“alkyl,” unless otherwise noted, is also meant to include thosederivatives of alkyl defined in more detail below, such as“heteroalkyl.” Alkyl groups which are limited to hydrocarbon groups aretermed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—C(═O)—CH₃, —CH₂—CH₂—CH₂—C(═O)—O—C(CH₃)—CH₃,—CH₂—CH₂—CH₂—C(═O)—N—CH(CH₃), —CH₂—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or aspart of another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)₂R′—represents both —C(O)₂R′— and —R′C(O)₂′.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Thus, a cycloalkylor heterocycloalkyl include saturated and unsaturated ring linkages.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include, but are not limited to, cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.Examples of heterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (preferably from 1 to 3 rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl and heteroaryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—CNR′R″R′″)═NR″″,—NR—CR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂in a number ranging from zero to (2m′+1), where m′ is the total numberof carbon atoms in such radical. R′, R″, R′″ and R″″ each preferablyindependently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1 to 3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a modulator of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: halogen, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system; and where R′, R″, R′″ and R″″are preferably independently selected from hydrogen, alkyl, heteroalkyl,aryl and heteroaryl. When a modulator of the invention includes morethan one R group, for example, each of the R groups is independentlyselected as are each R′, R″, R′″ and R″″ groups when more than one ofthese groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′−)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) —OH, —NH₂, —SH, —CN, —CF₃, oxy, halogen, unsubstituted        alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxy, —OH, —NH₂, —SH, —CN, —CF₃, halogen, unsubstituted            alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,            unsubstituted heterocycloalkyl, unsubstituted aryl,            unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxy, —OH, —NH₂, —SH, —CN, —CF₃, halogen,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from oxy, —OH, —NH₂, —SH, —CN,                —CF₃, halogen, unsubstituted alkyl, unsubstituted                heteroalkyl, unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, and unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2- to 20-membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein meansa group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl isa substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7membered heterocycloalkyl.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active modulators which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on themodulators described herein. When modulators of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such modulators with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When modulators of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such modulators with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science 66: 1-19 (1977)). Certain specific modulators ofthe present invention contain both basic and acidic functionalities thatallow the modulators to be converted into either base or acid additionsalts.

The neutral forms of the modulators are preferably regenerated bycontacting the salt with a base or acid and isolating the parentmodulator in the conventional manner. The parent form of the modulatordiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides modulators,which are in a prodrug form. Prodrugs of the modulators described hereinare those compounds or complexes that readily undergo chemical changesunder physiological conditions to provide the modulators of the presentinvention. Additionally, prodrugs can be converted to the modulators ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to themodulators of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

The term “ring” as used herein means a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Aring includes fused ring moities. The number of atoms in a ring aretypically defined by the number of members in the ring. For example, a“5- to 7-membered ring” means there are 5-7 atoms in the encirclingarrangement. The ring optionally includes a heteroatom. Thus, the term“5- to 7-membered ring” includes, for example pyridinyl, piperidinyl andthiazolyl rings.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to the radical of a molecule that is attached to anothermoiety.

The symbol

, whether utilized as a bond or displayed perpendicular to a bondindicates the point at which the displayed moiety is attached to theremainder of the molecule.

Certain modulators of the present invention can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present invention. Certainmodulators of the present invention may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present invention and are intended to be withinthe scope of the present invention.

Certain modulators of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention.

The modulators of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such modulators. For example, the modulators may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe modulators of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

II. Potassium Ion Channel Modulators

The invention provides potassium ion channel modulators that include apyrimidinyl moiety and a first and a second ring, each of said ringsbeing attached, either directly or through a linker, to the pyrimidinylmoiety. A potassium ion channel modulator of the present invention(“modulator of the present invention”) may be a compound (also referredto herein as a “compound of the present invention”) or metal ion complex(also referred to herein as a “complex of the present invention”), asdescribed below.

In one aspect, the potassium ion channel modulator is a compoundaccording to Formula (I):

In Formula (I), A and B are independently substituted or unsubstituted5- or 6-membered heterocycloalkyl, or substituted or unsubstituted 5- or6-membered heteroaryl. The symbol

The symbol

The symbol X is a bond, —CH₂—, or —NR⁴—. Y is a bond, —CH═N—NH—,—NH—CH₂—, or —NR⁵—. In some embodiments, X is a bond.

The symbols s and t are independently integers from 1 to 4. One of skillin the art will immediately recognize that where A is a 5-memberedheterocycloalkyl or 5-membered heteroaryl, then s is an integer from 1to 3; and where A is a 6-membered heterocycloalkyl or 6-memberedheteroaryl, then s is an integer from 1 to 4. Likewise, where B is a5-membered heterocycloalkyl or 5-membered heteroaryl, then t is aninteger from 1 to 3 and where B is a 6-membered heterocycloalkyl or6-membered heteroaryl, then t is an integer from 1 to 4.

The symbol k is an integer from 1 to 2.

R¹, R², and R³ are independently H, —OH, —NH₂, —NO₂, —SO₂NH₂, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted 3- to 7-membered cycloalkyl,substituted or unsubstituted 5- to 7-membered heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or —NR⁷R⁸.

R⁷ and R⁸ are independently H, halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted 5- to 7-membered cycloalkyl, substituted or unsubstituted5- to 7-membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁷ and R⁸ are optionally joinedtogether with the nitrogen to which they are attached to form asubstituted or unsubstituted 5- to 7-membered heterocycloalkyl, orsubstituted or unsubstituted heteroaryl.

R⁴ and R⁵ are independently H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstituted3- to 7-membered cycloalkyl, substituted or unsubstituted 5- to7-membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Where a plurality of R¹, R², and/or R³ groups are present, each R¹, R²,and/or R³ group is optionally different. For example, where s is greaterthan one, then each R¹ is optionally different; where k is greater thanone, then each R² is optionally different; and where t is greater thanone, then each R³is optionally different.

R¹, R², and R³ may optionally form part of a fused ring system. Forexample, two R¹ groups are optionally joined together with the atoms towhich they are attached to form a substituted or unsubstituted 5- to7-membered ring; two R² groups are optionally joined together with theatoms to which they are attached to form a substituted or unsubstituted5- to 7-membered ring; and two R³ groups are optionally joined togetherwith the atoms to which they are attached to form a substituted orunsubstituted 5- to 7-membered ring.

In some embodiments, A is substituted or unsubstituted heteroaryl. A mayalso be substituted or unsubstituted pyridinyl.

In other embodiments, A is

In Formula (III), R¹ and s are as defined above in the description ofFormula (I). In some embodiments, R¹ is selected from H, halogen, —NH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted 5- to 7-membered cycloalkyl,substituted or unsubstituted 5- to 7-membered heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

A may also be

R¹ is as described above in the discussion of Formula (I) of Formula(III). Alternatively, R¹ is halogen, or substituted or unsubstitutedalkyl. In a related embodiment, R¹ is Cl or unsubstituted alkyl (e.g.methyl, ethyl and the like). Thus, A may

In other embodiments, B is substituted or unsubstituted heteroaryl. Bmay also be substituted or unsubstituted pyridinyl. Alternatively, B is

In Formula (II), R³ and t are as defined above in the description ofFormula (I). In some embodiments of Formula (II), R³ is H, —NH₂, —NO₂,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted 3- to 7-memberedcycloalkyl, substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In another embodiment, R³ is Cl or —NR⁷R⁸. Ina related embodiment, R³ is —NH₂, —N(CH₃)₂,

In other embodiments, B is

R³ is as defined above in the description of Formula (I) or Formula(II). In other embodiments, R³ is substituted or unsubstituted alkyl(e.g. methyl, ethyl, and the like). Thus, B may be

R¹, R², and R³ may independently be H, —NH₂, —NO₂, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted 3- to 7-membered cycloalkyl, substituted orunsubstituted 5- to 7-membered heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or —NR⁷R⁸.

Alternatively, R¹ may be H, substituted or unsubstituted (C₁-C₁₀) alkyl,substituted or unsubstituted 2- to 10-membered heteroalkyl, orsubstituted or unsubstituted aryl. R′ may also be H, methyl, —NH₂, orunsubstituted phenyl.

R² may be H, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, or substituted or unsubstituted aryl. R² may also beH, Cl, methyl, —OCH₃, or unsubstituted pyridinyl. In some embodiments,R² is H or —OCH₃.

R³ may be H, —NH₂, —NO₂, halogen, substituted or unsubstituted (C₁-C₁)alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R³ may also be H, —NH₂, —NO₂, Cl, Br, F, methyl, phenyl,fluorophenyl, —CF₃, —OCH₃, dimethylamino, unsubstituted piperidine,p-methyl morpholino, unsubstituted pyrrolidinonyl, unsubstituted2-thiophenyl, unsubstituted 3-thiophenyl, unsubstituted furanyl, orn-methyl piperizinyl.

Alternatively, R³ is Cl or —NR⁷R⁸, where R⁷ and R⁸ are as defined above.

R³ may also be selected from R³ is Cl, —NH₂, —N(CH₃)₂,

In some embodiments, X is a bond. In a related embodiment k is 2. In afurther related embodiment, R² is H or —OCH₃.

In other embodiments, Y is NH. In a related embodiment, t is 1. In afurther related embodiment, B is

R³ is as defined above in the description of Formula (II). In anotherrelated embodiment, B is

The symbol Y may also represent a bond. In a related embodiment, k is 1.In another related embodiment, R² is H.

X may be NH. In some related embodiments, A is

R¹ and s are as defined above in the description of Formula (III). Inanother related embodiment, A is

In some embodiments, each substituted moiety described above for thecompounds of the present invention is substituted with at least onesubstituent group. The term “substituent group,” as used herein, isdefined in detail above in the “Abbreviations and Definitions” section.More specifically, in some embodiments, each substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, and/or substituted heteroaryldescribed above are substituted with at least one substituent group.Each substituent group is optionally different. In other embodiments, atleast one or all of these groups are substituted with at least onesize-limited substituent group. Alternatively, at least one or all ofthese groups are substituted with at least one lower substituent group.Size-limited substituent groups and lower substituent groups are bothdefined in detail above in the “Abbreviations and Definitions” section.

In other embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₂₀ alkyl, and each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2- to20-membered heteroalkyl.

Alternatively, each substituted or unsubstituted alkyl is a substitutedor unsubstituted C₁-C₈ alkyl, and each substituted or unsubstitutedheteroalkyl is a substituted or unsubstituted 2- to 8-memberedheteroalkyl.

In another embodiment, the present invention provides a metal complexmodulator, comprising a polyvalent metal ion (e.g. iron, zinc, copper,cobalt, manganese, and nickel) and a polydentate component of a metalion chelator. The polydentate component is a compound of the presentinvention (e.g. a compound of Formulae (I), (II), or (III)). The metalcomplexes of the present invention are potassium ion channel modulators.

In some embodiments, the metal complex modulator has the structure

In Formula (IV), M is a polyvalent metal ion (e.g. iron, zinc, copper,cobalt, manganese, and nickel). W² and Z² are —N═. W¹, Z¹, R¹, R², R³,X, Y, s, k, t, A, and B are as defined above in the description of thecompound of Formula (I).

Also within the scope of the present invention are compounds of theinvention that function as poly- or multi-valent species, including, forexample, species such as dimers, trimers, tetramers and higher homologsof the compounds of the invention or reactive analogues thereof. Thepoly- and multi-valent species can be assembled from a single species ormore than one species of the invention. For example, a dimeric constructcan be “homo-dimeric” or “heterodimeric.” Moreover, poly- andmulti-valent constructs in which a compound of the invention or reactiveanalogues thereof are attached to an oligomeric or polymeric framework(e.g., polylysine, dextran, hydroxyethyl starch and the like) are withinthe scope of the present invention. The framework is preferablypolyfunctional (i.e. having an array of reactive sites for attachingcompounds of the invention). Moreover, the framework can be derivatizedwith a single species of the invention or more than one species of theinvention.

Preparation of Potassium Ion Channel Modulators

The following exemplary schemes illustrate methods of preparing themodulators of the present invention. These methods are not limited toproducing the compounds shown, but can be used to prepare a variety ofmodulators such as the compounds and complexes described above. Themodulators of the invention can also be produced by methods notexplicitly illustrated in the schemes but are well within the skill ofone in the art. The modulators can be prepared using readily availablestarting materials or known intermediates.

In the following schemes, the symbol Y is independently selected fromCH₂, N, S, and O. The symbol D is independently selected from H, —OH,—NH₂, —NO₂, —SO₂NH₂, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstituted3- to 7-membered cycloalkyl, substituted or unsubstituted 5- to7-membered heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. The symbol p is an integerindependently selected from 1-5. The symbol q is an integerindependently selected from 0-5.

The substituents of the pyrimidinyl compounds of the invention can beproduced through the methods outlined in Schemes 1-8.

In one embodiment, the substituents of the invention compriseamino-substituted heteroaryl moieties as shown in Schemes 1-6.

In Scheme 1, compound 1 is reacted with benzylamine, followed bydebenzylation in concentrated sulfuric acid to produce 2.

An alternative route to producing compound 2 is shown in Scheme 2.

In Scheme 2, a compound 3 is reduced to form compound 2.

Substituents can be added to the amino-substituted heteroaryl moietiesas described in Schemes 3-6.

In Scheme 3, compound 4 is iodinated to produce a halosubstituted2-amino-aza-heterocycle 5. This compound is reacted with a boronic acid6 in the presence of tris(dibenzylideneacetone)dipalladium(0)(Pd₂(dba)₃), and PPh₃ in toluene, ethanol, and water to produce 2.

In another example, amino substituents can be added to the heteroarylmoieties in the following manner.

In Scheme 4, an iodo-substituted 2-amino-aza-heterocycle 5 is reactedwith an amine 7 or amide using copper catalyzed coupling chemistry togenerate a 2-amino-aza-heterocycle 8.

In Scheme 5, a bromo-substituted 2-nitro-aza-heterocycle 9 is reactedwith an amine 7 or amide using palladium-catalyzed coupling chemistry togenerate an aminosubstituted 2-nitro-aza-heterocycle 10. The nitroadduct is reduced to an amino adduct 8 by a palladium catalyzedhydrogenation.

In Scheme 6, a bromo-substituted 2-nitro-aza-heterocycle 9 is reactedwith an amine 7 or amide using copper catalyzed coupling chemistry togenerate an aminosubstituted 2-nitro-aza-heterocycle 10. The nitroadduct is reduced to an amino adduct 8 by a palladium catalyzedhydrogenation.

In one embodiment, the substituents of the invention comprisehalo-substituted heteroaryl moieties as shown in Scheme 7.

In Scheme 7, compound 11 or 2 or 8 is halogenated by diazotizationfollowed by sodium nitrite in the presence of acid containing halogen at0° C. to produce compound 12.

In another embodiment, the substituents of the invention comprisestannyl-substituted heteroaryl moieties as shown in Scheme 8.

In Scheme 8, compound 13 is stannylated with n-butyllithium to producecompound 14.

Stannyl-substituted and halo-substituted heteroaryl moieties can beadded to a pyrimidine compound of the invention through the methodsoutlined in Scheme 9.

In Scheme 9, addition of compound 14 to a 2,4-dichloropyrimidine 15 inthe presence of a palladium catalyst in toluene produces compound 16.

An alternative way of producing compound 16 is illustrated in Scheme 10.

In Scheme 10, compound 12 or 14 is reacted with 2-chloropyrimidine 17 inthe presence of n-butyllithium to produce 16.

Amino-substituted heteroaryl moieties can be added to a pyrimidinecompound of the invention through the methods outlined in Scheme 11.

In Scheme 11, compound 2 or 8 is mixed with sodium hydride to facilitatethe nucleophilic addition of 2 or 8 to compound 15 to form compound 18.

Bis-substituted pyrimidines are produced from the method of Scheme 12.

In Scheme 12, compound 2 or 8 is mixed with sodium hydride to facilitatethe nucleophilic addition of 2 or 8 to compound 16. The final product isa bis-substituted pyrimidine 19.

An alternative method of producing bis-substituted pyrimidine compoundsof the invention is illustrated by Scheme 13.

In Scheme 13, compound 14 is added to compound 18 in the presence of apalladium catalyst in toluene to produce the hydrochloride salt of abis-substituted pyrimidine 20.

A method of making substituted pyrimidines with a fused aromatic ring isdescribed in Scheme 14.

In Scheme 14, compound 21 is reacted with compound 22 in the presence oftriethylamine in THF to provide compound 23.

The pyrimidine ring can be formed by a method outlined in Scheme 15.

In Scheme 15, addition of a base causes the intramolecular cyclizationof compound 23 to form compound 24.

The OH at the 4-position of the pyrimidine ring can be converted into achlorine by the procedure outlined in Scheme 16.

In Scheme 16, compound 24 is reacted with phosphorus oxychloride inorder to produce compound 25.

A new substituent can be added to the 4-position of the pyrimidine ringas shown in Scheme 17.

In Scheme 17, compound 2 or 8 is mixed with sodium hydride to facilitatethe nucleophilic addition of 2 or 8 to compound 25. The product is abis-substituted pyrimidine 26.

An alternative method of making substituted pyrimidines with a fusedaromatic ring is described in Scheme 18.

Compound 27 is reacted with stannyl derivative 14 in order to producecompound 28. Compound 28 is then reacted with compound 2 or 8. Theproduct is a bis-substituted pyrimidine 29.

The compounds of the invention also include metal complexes. These metalcomplexes comprise a polyvalent metal ion and a pyrimidinyl compound ofthe invention. In an exemplary embodiment, the polyvalent metal ion canbe a transition metal. In another exemplary embodiment, the polyvalentmetal ion is a member selected from iron, zinc, copper, cobalt,manganese, and nickel.

A method of creating metal-pyrimidinyl complexes of the invention isoutlined in Scheme 19.

In Scheme 19, compound 19 or 20 or 26 or 29, or combinations thereof,are first mixed with FeClO₄ in ether. To this mixture is addedtriethylamine which then forms metal complex 30.

III. Assays for Modulators of Potassium Ion Channels

SK monomers as well as SK alleles and polymorphic variants are subunitsof potassium ion channels. The activity of a potassium ion channelcomprising SK subunits can be assessed using a variety of in vitro andin vivo assays, e.g., measuring current, measuring membrane potential,measuring ion flow, e.g., potassium or rubidium, measuring potassiumconcentration, measuring second messengers and transcription levels,using potassium-dependent yeast growth assays, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patchClampelectrophysiology.

Furthermore, such assays can be used to test for inhibitors andactivators of channels comprising SK. The SK family of channels isimplicated in a number of disorders that are targets for a therapeuticor prophylactic regimen, which functions by blockade or inhibition ofone or more members of the SK channel family. The modulators and methodsof the invention are useful to treat central or peripheral nervoussystem disorders (e.g., migraine, ataxia, Parkinson's disease, bipolardisorders, trigeminal neuralgia, spasticity, mood disorders, braintumors, psychotic disorders, myokymia, seizures, epilepsy, hearing andvision loss, psychosis, anxiety, depression, dementia, memory andattention deficits, Alzheimer's disease, age-related memory loss,learning deficiencies, anxiety, traumatic brain injury, dysmenorrhea,narcolepsy and motor neuron diseases). The modulators of the inventionare also useful in treating disease states such as gastroesophogealreflux disorder and gastrointestinal hypomotility disorders, irritablebowel syndrome, secretory diarrhea, asthma, cystic fibrosis, chronicobstructive pulmonary disease and rhinorrhea, convulsions, vascularspasms, coronary artery spasms, renal disorders, polycystic kidneydisease, bladder spasms, urinary incontinence, bladder outflowobstruction, ischemia, cerebral ischemia, ischemic heart disease, anginapectoris, coronary heart disease, Reynaud's disease, intermittentclaudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonicmuscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia,premature labor, baldness, cancer, and immune suppression.

Modulators of the potassium ion channels are tested using biologicallyactive SK, either recombinant or naturally occurring, or by using nativecells, like cells from the nervous system expressing an SK channel. SKchannels can be isolated, co-expressed or expressed in a cell, orexpressed in a membrane derived from a cell. In such assays, SK isexpressed alone to form a homomeric potassium ion channel or isco-expressed with a second subunit (e.g., another SK family member) soas to form a heteromeric potassium ion channel. Modulation is testedusing one of the in vitro or in vivo assays described above. Samples orassays that are treated with a potential potassium ion channel inhibitoror activator are compared to control samples without the test modulator,to examine the extent of modulation. Control samples (untreated withactivators or inhibitors) are assigned a relative potassium ion channelactivity value of 100. Inhibition of channels comprising SK is achievedwhen the potassium ion channel activity value relative to the control isless than 70%, preferably less than 40% and still more preferably, lessthan 30%. Modulators that decrease the flow of ions will cause adetectable decrease in the ion current density by decreasing theprobability of a channel comprising SK being open, by decreasingconductance through the channel, and decreasing the number or expressionof channels.

Changes in ion flow may be assessed by determining changes inpolarization (i.e., electrical potential) of the cell or membraneexpressing the potassium ion channel. A preferred means to determinechanges in cellular polarization is by measuring changes in current orvoltage with the voltageClamp and patchClamp techniques, using the“cell-attached” mode, the “inside-out” mode, the “outside-out” mode, the“perforated cell” mode, the “one or two electrode” mode, or the “wholecell” mode (see, e.g., Ackerman et al., New Engl. J. Med. 336: 1575-1595(1997)). Whole cell currents are conveniently determined using thestandard methodology (see, e.g., Hamil et al., Pflugers. Archiv. 391: 85(1981)). Other known assays include: radiolabeled rubidium flux assaysand fluorescence assays using voltage-sensitive dyes (see, e.g.,Vestergarrd-Bogind et al., J. Membrane Biol. 88: 67-75 (1988); Daniel etal., J. Pharmacol. Meth. 25: 185-193 (1991); Holevinsky et al., J.Membrane Biology 137: 59-70 (1994)). Assays for modulators capable ofinhibiting or increasing potassium flow through the channel proteins canbe performed by application of the modulators to a bath solution incontact with and comprising cells having a channel of the presentinvention (see, e.g., Blatz et al., Nature 323: 718-720 (1986); Park, J.Physiol. 481: 555-570 (1994)). Generally, the modulators to be testedare present in the range from about 1 pM to about 100 mM, preferablyfrom about 1 pM to about 1 μM.

The effects of the test modulators upon the function of the channels canbe measured by changes in the electrical currents or ionic flow or bythe consequences of changes in currents and flow. Changes in electricalcurrent or ionic flow are measured by either increases or decreases inflow of ions such as potassium or rubidium ions. The cations can bemeasured in a variety of standard ways. They can be measured directly byconcentration changes of the ions or indirectly by membrane potential orby radio-labeling of the ions. Consequences of the test modulator on ionflow can be quite varied. Accordingly, any suitable physiological changecan be used to assess the influence of a test modulator on the channelsof this invention. The effects of a test modulator can be measured by atoxin-binding assay. When the functional consequences are determinedusing intact cells or animals, one can also measure a variety of effectssuch as transmitter release (e.g., dopamine), hormone release (e.g.,insulin), transcriptional changes to both known and uncharacterizedgenetic markers (e.g., northern blots), cell volume changes (e.g., inred blood cells), immunoresponses (e.g., T cell activation), changes incell metabolism such as cell growth or pH changes, and changes inintracellular second messengers such as calcium, or cyclic nucleotides.

IV. Pharmaceutical Compositions for use as Potassium Ion ChannelModulators

In another aspect, the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and amodulator of the present invention (e.g. a compound of the presentinvention or a complex of the present invention).

Formulation of the Modulators

The modulators of the present invention can be prepared and administeredin a wide variety of oral, parenteral and topical dosage forms. Thus,the modulators of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, themodulators described herein can be administered by inhalation, forexample, intranasally. Additionally, the modulators of the presentinvention can be administered transdermally. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and either a modulator, or apharmaceutically acceptable salt of a modulator.

For preparing pharmaceutical compositions from the modulators of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive modulator. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active modulator withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

V. Methods for Decreasing Ion Flow in Potassium Ion Channels

In yet another aspect, the present invention provides a method fordecreasing ion flow through potassium ion channels in a cell, comprisingcontacting the cell with a potassium ion channel modulating amount of amodulator of the present invention.

In an exemplary embodiment, the potassium ion channels comprise at leastone SK subunit.

The methods provided in this aspect of the invention are useful in thetherapy of conditions mediated through potassium ion flow, as well asfor the diagnosis of conditions that can be treated by decreasing ionflow through potassium ion channels. Additionally the methods are usefulfor determining if a patient will be responsive to therapeutic agentswhich act by modulating potassium ion channels. In particular, apatient's cell sample can be obtained and contacted with a potassium ionchannel modulator described above and the ion flow can be measuredrelative to a cell's ion flow in the absence of the modulator. Adecrease in ion flow will typically indicate that the patient will beresponsive to a therapeutic regiment of the modulator.

VI. Methods for Treating Conditions Mediated by Potassium Ion Channels

In still another aspect, the present invention provides a method fortreating a disease through the modulation of potassium ion flow throughpotassium ion channels. The modulation may be activation or inhibitionof the potassium ion flow. Thus, the modulators of the present inventionmay be inhibitors of potassium ion flow through potassium ion channels(i.e. decrease the flow relative to the absence of the modulator) oractivators of potassium ion flow through potassium ion channels (i.e.increase the flow relative to the absence of the modulator).

The modulators are useful in the treatment of central or peripheralnervous system disorders (e.g., migraine, ataxia, Parkinson's disease,bipolar disorders, trigeminal neuralgia, spasticity, mood disorders,brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearingand vision loss, psychosis, anxiety, depression, dementia, memory andattention deficits, Alzheimer's disease, age-related memory loss,learning deficiencies, anxiety, traumatic brain injury, dysmenorrhea,narcolepsy and motor neuron diseases), and as neuroprotective agents(e.g., to prevent stroke and the like). The modulators of the inventionare also useful in treating disease states such as gastroesophogealreflux disorder and gastrointestinal hypomotility disorders, irritablebowel syndrome, secretory diarrhea, asthma, cystic fibrosis, chronicobstructive pulmonary disease and rhinorrhea, convulsions, vascularspasms, coronary artery spasms, renal disorders, polycystic kidneydisease, bladder spasms, urinary incontinence, bladder outflowobstruction, ischemia, cerebral ischemia, ischemic heart disease, anginapectoris, coronary heart disease, Reynaud's disease, intermittentclaudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonicmuscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia,premature labor, baldness, cancer, and immune suppression. This methodinvolves administering, to a patient, an effective amount (e.g. atherapeutically effective amount) of a modulator of the presentinvention (a compound or complex of the present invention).

Thus, the present invention provides a method of decreasing ion flowthrough potassium ion channels in a cell. The method includes contactingthe cell with a potassium ion channel-modulating amount of a modulatorof the present invention. In some embodiments, the potassium ion channelincludes at least one SK subunit. The cell may be isolated or form partof a organ or organism.

The modulators provided herein find therapeutic utility via modulationof potassium ion channels in the treatment of diseases or conditions.The potassium ion channels that are typically modulated are describedherein. As noted above, these channels may include homomultimers andheteromultimers.

In therapeutic use for the treatment of neurological conditions, themodulators utilized in the pharmaceutical method of the invention areadministered at the initial dosage of about 0.001 mg/kg to about 1000mg/kg daily. A daily dose range of about 0.1 mg/kg to about 100 mg/kg ismore typical. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the modulator being employed. Determination of the properdosage for a particular situation is within the skill of thepractitioner. Generally, treatment is initiated with smaller dosages,which are less than the optimum dose of the modulator. Thereafter, thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day.

The materials and methods of the present invention are furtherillustrated by the examples which follow. These examples are offered toillustrate, but not to limit, the claimed invention.

EXAMPLES

General

In the examples below, unless otherwise stated, temperatures are givenin degrees Celsius (° C.); operations were carried out at room orambient temperature, “rt,” or “RT,” (typically a range of from about18-25° C.); evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (typically, 4.5-30 mm Hg) with a bathtemperature of up to 60° C.; the course of reactions was typicallyfollowed by thin layer chromatography (TLC) and reaction times areprovided for illustration only; melting points are uncorrected; productsexhibited satisfactory ¹H-NMR and/or microanalytical data; yields areprovided for illustration only; and the following conventionalabbreviations are also used: mp (melting point), L (liter(s)), mL(milliliters), mmol (millimoles), g (grams), mg (milligrams), min(minutes), and h (hours).

Unless otherwise specified, all solvents (HPLC grade) and reagents werepurchased from suppliers and used without further purification.Reactions were conducted under a blanket of argon unless otherwisestated. Analytical TLC was performed on Whatman Inc. 60 silica gelplates (0.25 mm thickness). Compounds were visualized under UV lamp (254nM) or by developing with KMnO₄/KOH, ninhydrin or Hanessian's solution.Flash chromatography was done using silica gel from Selectro Scientific(particle size 32-63). ¹H NMR, ¹⁹F NMR and ¹³C NMR spectra were recordedon a Varian 300 machine at 300 MHz, 282 MHz and 75.7 MHz, respectively.Melting points were recorded on a Electrothermal IA9100 apparatus andwere uncorrected.

Example 1

Preparation of 2 from 1

1.1 Nucleophilic Replacement

A mixture of 14.7 mmol of 1 and 75 mmol of benzylamine was heated at220° C. for 6 h in a sealed tube. The reaction mixture was concentratedin vacuo and the residue was purified by column chromatography on silicagel to give 7.0 mmol of N-benzyl pyridine-2-amine.

A solution of 6.9 mmol of N-benzyl pyridin-2-amine in 15 mL of conc.H₂SO₄ was stirred at 80° C. for 1 h. The reaction mixture was pouredinto crushed ice and neutralized with 28% NH₄OH. The mixture wasextracted with AcOEt and the organic phase was washed with brine, driedover MgSO₄, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give 5.0 mmol of 2.

1.2 Results

Analytical data for exemplary compounds of structure 2 are providedbelow.

1.2.a 5-Hexylpyridin-2-ylamine

¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=2.2 Hz, 1H), 7.26 (dd, J₁=8.4 Hz,J₂=2.2 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H), 4.27 (br s, 2H), 2.45 (d, J=6.6Hz, 1H), 1.48-1.56 (m, 2H),1.27-1.35 (m, 6H), 0.88 (t, J=6.6 Hz, 3H); MSm/z: 178 (M+1).

1.2. b 5-tert-Butylpyridin-2-ylamine

¹H NMR (300 MHz, CDCl₃) δ 8.08 (d, J=2.6 Hz, 1H), 7.47 (dd, J,=8.6 Hz,J₂=2.6 Hz, 1H), 6.47 (dd, J₁=8.6 Hz, J₂=0.7 Hz, 1H), 1.28 (s, 9H); MSm/z: 151 (M+1).

1.2. c 5-[2-(Benzyloxy)ethyl]pyridin-2-ylamine

¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J=1.8 Hz, 1H), 7.25-7.37 (m, 6H),6.45 (dd, J₁=8.4 Hz, J₂=0.7 Hz, 1H), 4.51 (s, 2H), 4.31 (br s, 2H), 3.62(t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H); MS m/z: 228 (M+1).

1.2.d 1-(6-Aminopyridin-3-yl)-4-methylpiperazin-2-one

¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (d, J=2.4 Hz, 1H), 7.28 (dd, J₃=8.7 Hz,J₂=2.7 Hz, 1H), 6.43 (d, J=8.8 Hz, 1H), 5.97 (br s, 2H), 3.53 (t, J=5.4Hz, 2H), 3.06 (s, 2H), 2.68 (t, J=5.4 Hz, 2H), 2.26 (s, 3H); MS m/z: 279(M+1).

Example 2

Preparation of 2 from 3

2.1 Catalytic Reduction

A solution or a suspension of 15 mmol of 3 and 0.5 g of Pd/C (10%) in150 mL of methanol was stirred overnight under H₂ (1 atm). Afterfiltering through celite, the solution was concentrated under a reducedpressure to give 15 mmol of 2.

Example 3

Preparation of 2

3.1 Iodination of 4

A mixture of 240 mmol of 4, 58 mmol of HIO₄, and 240 mmol of I₂ in 60 mLof water, 4 mL of concentrated H₂SO₄, and 200 mL of acetic acid wasstirred at 80° C. for 4 h. Excess I₂ was neutralized by the addition of200 mL of saturated Na₂S₂O₃ solution. The resulting aqueous solution wasextracted with EtOAc. The organic phase was washed with saturated NaCl,dried over MgSO₄, and concentrated under a reduced pressure. The residuewas purified by column chromatography on silica gel to give 136 mmol of5.

3.2 Suzuki Cross Coupling

A mixture of 15 mmol of 5, 15 mmol of 6, 0.35 mmol of Pd₂(dba)₃, and 2.4mmol of PPh₃ in 40 mL of toluene, 20 mL of ethanol, and 20 mL of waterwas refluxed overnight under N₂. The reaction mixture was diluted with300 mL of ethyl acetate and the organic solution was washed withsaturated NaCl, dried over MgSO₄, and concentrated under a reducedpressure. The residue was purified by column chromatography on silicagel to give 13.1 mmol of 2.

3.3 Results

Analytical data for exemplary compounds of structure 2 are providedbelow.

3.3. a 5-(2-Methoxy-phenyl)-pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 7.99 (d, J=2.0 Hz, 1H), 7.48 (dd, J₁=8.6 Hz,J₂=2.3 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.21 (d, J=6.1 Hz, 1H), 7.03 (d,J=8.0 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 5.94 (s,2H), 3.73 (s, 3H); MS m/z: 201 (M+1).

3.3. b (5-Methyl-furan-2-yl)-pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=2.0 Hz, 1H), 7.63-7.52 (m, 2H),6.48 (d, J=3.2 Hz, 1H), 6.43 (d, J=8.7 Hz, 1H), 6.08 (s, 2H), 2.27 (s,3H); MS m/z: 175 (M+1).

3.3.c [3,3′]Bipyridinyl-6-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 8.78 (d, J=2.1 Hz, 1H), 8.44 (dd, J₁=4.9 Hz,J₂=1.6 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H), 7.94 (dt, J₁=8.0 Hz, J₂=1.9 Hz,1H), 7.73 (dd, J₁=8.7 Hz, J₂=2.6 Hz, 1H), 7.38 (dd, J₁=8.7 Hz, J₂=2.6Hz, 1H), 6.52 (d, J=8.7 Hz, 1H), 6.17 (s, 2H); MS m/z: 172 (M+1).

3.3. d 5-(4-Fluoro-phenyl)-4-methyl-pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (s, 1H), 7.30 (dd, J₁=8.5 Hz, J₂=5.7Hz, 2H), 7.19 (t, J=8.9 Hz, 2H), 6.33 (s, 1H), 5.87 (s, 2H), 2.07 (s,3H); MS m/z: 203 (M+1).

3.3. e 5-(3-Fluoro-phenyl)-pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.6 Hz,1H), 7.42-7.38 (m, 3H), 7.08-7.01 (m, 1H), 6.49 (d, J=8.6 Hz, 1H), 6.15(s, 2H); MS m/z: 189 (M+1).

3.3f 5-Thiophen-2-yl-pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (d, J=2.3 Hz, 1H), 7.61 (d, J=8.5 Hz,7.37 (d, J=5.1 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.04 (t, J=4.7 Hz, 1H),6.45 (d, J=8.7 Hz, 1H), 6.14 (s, 2H); MS m/z: 177 (M+1).

Example 4

Preparation of 8 from 5

4.1 Ullmann Cross-Coupling

To a solution of 50.0 mmol of 5 and 60.0 mmol of 7 in 50.0 mL of1,4-dioxane was added 0.500 mmol of copper (I) iodide followed by theaddition of 100 mmol of K₃PO₄ and 5 mmol of trans-cyclohexanediaamine,then the resulting mixture was stirred at 100° C. for 16 h. The reactionmixture was cooled to rt and diluted with 500 mL of H₂O. The resultingaqueous solution was extracted with CHCl₃. The organic phase was washedwith saturated NaCl, dried over MgSO₄ and concentrated in vacuo. Thecrude product was purified by column chromatography to give 43.4 mmol of8.

4.2 Results

Analytical data for exemplary compounds of structure 8 are providedbelow.

4.2. a tert-Butyl 4-(6-aminopyridin-3-yl)-3-oxopiperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.97-8.00 (m, 1H), 7.35-7.40 (m, 1H),6.50-6.54 (m, 1H), 4.54 (br s, 2H), 4.24 (s, 2H), 3.65-3.69 (m, 2H),3.75-3.80 (m, 2H), 1.50 (s, 9H); MS m/z: 293 (M+1).

4.2. b 5-(4-Methyl-1,4-diazepan-1-yl)pyridin-2-ylamine

¹H NMR (400 MHz, DMSO-d₆) δ 7.46 (d, J=3.5 Hz, 1H), 6.95 (dd, J₃=8.8 Hz,J₂=3.5 Hz, 1H), 6.38 (d, J=8.8 Hz, 1H), 5.04 (br s, 2H), 3.26-3.40 (m,4H), 2.53-2.59 (m, 2H), 2.41-2.47 (m, 2H), 2.24 (s, 3H), 1.78-1.90 (m,2H); MS m/z: 207 (M+1).

4.2.c 4-(6-Aminopyyridin-3-yl)-1-methyl-1,4-diazepan-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (d, J=2.9 Hz, 1H), 7.18 (dd, J₃=8.8 Hz,J₂=2.9 Hz, 1H), 6.41 (d, J=8.8 Hz, 1H), 5.90 (br s, 2H), 3.64-3.71 (m,2H), 2.51-2.62 (m, 4H), 2.26 (s, 3H); MS m/z: 221(M+1).

4.2. d tert-Butyl4-(6-aminopyridin-3-yl)-5-oxo-1,4-diazepane-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=2.8 Hz, 1H), 7.29 (dd, J₁=8.8 Hz,J₂=2.8 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.54 (br s, 2H), 3.71-3.75 (m,6H), 2.80-2.83 (m, 2H), 1.49 (s, 9H); MS m/z: 307 (M+1).

Example 5

Preparation of 8

5.1 Buchwald Cross-Coupling

A mixture of 30 mmol of 9, 30 mmol of 7, 0.04 mmol of Pd₂(dba)₃, 0.08mmol of rac-2,2′-bis(phenylphosphino)-1,1′-binaphthyl (BINAP), and 42mmol of Cs₂CO₃ in 100 mL of dry toluene was stirred at 80° C. for twodays under N₂. The reaction mixture was diluted with 400 mL of ethylacetate and the organic solution was washed with saturated NaCl, driedover MgSO₄, and concentrated under reduced pressure. The residue wascrystallized in ethyl acetate to yield 15.8 mmol of 10.

A solution or a suspension of 15 mmol of 10 and 0.5 g of Pd/C (10%) in150 mL of methanol was stirred overnight under H₂ (1 atm). Afterfiltering through celite, the solution was concentrated under a reducedpressure to give 15 mmol of 8.

5.2 Results

Analytical data for exemplary compounds of structure 8 are providedbelow.

5.2.a 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=2.7 Hz, 1H), 7.13 (dd, J₁=8.9 Hz,J₂=2.9 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H), 5.36 (s, 2H), 2.89 (t, J=5.0 Hz,4H), 2.40 (t, J=5.0 Hz, 4H), 2.18 (s, 3H); MS m/z: 193 (M+1).

5.2.b 4-Methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=2.8 Hz, 1H), 7.11 (dd, J₁=8.9 Hz,J₂=3.0 Hz, 1H), 6.35 (d, J=8.8 Hz, 1H), 5.34 (s, 2H), 3.26 (d, J=12.0Hz, 2H), 2.45 (dt, J₁=9.3 Hz, J₂=4.2 Hz, 2H), 1.64 (d, J=12.5 Hz, 2H),1.4-1.3 (m, 1H), 1.44-1.28 (m, 2H), 0.90 (d, J=6.5 Hz, 3H); MS m/z: 192(M+1).

5.2.c 1-(6-Aminopyridin-3-yl)-pyrrolidin-2-one

¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (d, J=2.6 Hz, 1H), 7.63 (dd, J₁=8.9 Hz,J₂=2.6 Hz, 1H), 6.42 (d, J=8.9 Hz, 1H), 5.83 (s, 2H), 3.70 (t, J=7.0 Hz,2H), 2.39 (t, J₁=7.8 Hz, 2H), 2.01 (dd, J₁=7.1 Hz, J₂=7.9 Hz, 2H); MSm/z: 178 (M+1).

5.2.d 1-(6-Aminopyridin-3-yl)piperidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (d, J=2.4 Hz, 1H), 7.24 (dd, J₃=8.8 Hz,J₂=2.4 Hz, 1H), 6.42 (d, J=8.8 Hz, 1H), 5.90 (br s, 2H), 3.49 (t, J=6.0Hz, 2H), 2.34 (t, J=6.0 Hz, 2H), 1.77-1.85 (m, 4H); MS m/z: 192 (M+1).

5.2.e 1-(6-Aminopyridin-3-yl)piperidin-4-ol

¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=2.4 Hz, 1H), 7.14 (dd, J₁=9.2 Hz,J₂=2.4 Hz, 2H), 6.38 (d, J=9.2 Hz, 1H), 5.34 (br s, 2H), 4.63 (1H, d,J=4.4 Hz), 3.50-3.57 (m, 1H), 3.18-3.23 (m, 2H), 2.59-2.65 (m, 2H),1.76-1.83 (m, 2H), 1.44-1.54 (m, 2H); MS m/z: 194 (M+1).

5.2f 5-Piperidin-1-ylpyridin-2-ylamine

¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=2.8 Hz, 1H), 7.17 (dd, J₁=8.8 Hz,J₂=2.8 Hz, 1H), 6.47 (dd, J₃=8.0 Hz, J₂=0.8 Hz, 1H), 4.11 (br s, 2H),2.98 (d, J=5.2 Hz, 2H), 2.97 (d, J=5.2 Hz, 2H), 1.68-1.74 (m, 4H),1.51-1.57 (m, 2H); MS m/z: 178 (M+1).

5.2.g 5-(4-Isopropylpiperazin-1-yl)pyridin-2-ylamine

¹H NMR (300 MHz, DMSO-d₆) δ 7.55-7.60 (m, 1H), 7.10-7.17 (m, 1H),6.35-6.42 (m, 1H), 5.34 (br s, 2H), 2.85-2.94 (m, 4H), 2.50-2.70 (m,5H), 0.95-1.02 (m, 6H); MS m/z: 221 (M+1).

5.2.h tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=2.8 Hz, 1H), 7.17 (dd, J₁=8.8 Hz,J₂=2.8 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 4.21 (br s, 2H), 3.57 (t, J=5.2Hz, 4H), 2.96 (t, J=5.2 Hz, 4H), 1.48 (s, 9H); MS m/z: 279 (M+1).

5.2.i 1-(6-Aminopyridin-3-yl)-4-methylpiperazin-2-one

¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (d, J=2.4 Hz, 1H), 7.28 (dd, J₃=8.7 Hz,J₂=2.7 Hz, 1H), 6.43 (d, J=8.8 Hz, 1H), 5.97 (br s, 2H), 3.53 (t, J=5.4Hz, 2H), 3.06 (s, 2H), 2.68 (t, J=5.4 Hz, 2H),2.26 (s, 3H); MS m/z: 207(M+1).

5.2j 5-[3-(Dimethylamino)pyrrolidin-1-yl]pyridin-2-ylamine

¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=2.8 Hz, 1H), 6.83 (dd, J₃=8.8 Hz,J₂=2.8 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.96 (br s, 2H), 3.24-3.41 (m,3H), 3.09 (t, J=8.0 Hz, 1H), 2.82-2.90 (m, 1H), 2.35 (s, 6H), 2.14-2.22(m, 1H), 1.86-1.96 (m, 1H); MS m/z: 206 (M+1).

5.2.k N⁵-I-Azabicyclo[2.2.2]oct-3-ylpyridin-2,5-yldiamine

¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=2.8 Hz, 1H), 6.86 (dd, J₃=8.4 Hz,J₂=2.8 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.00 (br s, 2H), 3.34-3.37 (m,1H), 2.80-2.90 (m, 4H), 2.50-2.53 (m, 1H), 1.23-1.97 (m, 6H); MS m/z:218 (M+1).

5.2.l 5-(2,4,5-Trimethylpiperazin-1-yl)pyridin-2-ylamine

¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=2.8 Hz, 1H), 7.30 (dd, J₁=8.8 Hz,J₂=2.8 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 4.29 (br s, 2H), 3.06 (m, 1H),2.86 (dd, J₁11.2 Hz, J₂=3.2 Hz, 2H), 2.66 (m, 1H), 2.33 (m, 4H), 2.12(t, J=10.8 Hz, 1H), 1.07 (d, J=6.4 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H); MSm/z: 221 (M+1).

5.2.m N⁵-Methyl-N⁵-(1-methylpyrrolidin-3-yl)pyridin-2,5-yldiamine

¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=2.8 Hz, 1H), 7.16 (dd, J₁=8.8 Hz,J₂=2.8 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 4.12 (br s, 2H), 3.97-4.04 (m,1H), 2.72 (s, 3H); 2.60-2.70 (m, 2H), 2.50-2.56 (m, 2H), 2.34 (s, 3H),2.04-2.10 (m, 1H), 1.77-1.83 (m, 1H); MS m/z: 207 (M+1).

5.2.n 5-(3-Methylpiperazin-1-yl)pyridin-2-ylamine

¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=2.8 Hz, 1H), 7.15 (dd, J₃=8.8 Hz,J₂=2.8 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 4.33 (m, 1H), 4.21 (br s, 2H),3.92-3.96 (m, 1H), 3.19-3.26 (m, 2H), 3.08-3.11 (m, 1H), 2.82 (dd,J₃=11.6 Hz, J₂=4.0 Hz, 1H), 2.61-2.68 (m, 1H), 1.48 (s, 9H), 1.32 (d,J=6.8 Hz, 3H); MS m/z: 293 (M+1).

5.2.o 5-(3,5-Dimethylpiperazin-1-yl)pyridin-2-ylamine

¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.8 Hz, 1H), 7.16 (dd, J₃=8.8 Hz,J₂=2.8 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.18-4.24 (m, 2H), 3.08-3.11 (m,2H), 2.80 (dd, J₁=11.6 Hz, J₂=4.0 Hz, 1H), 1.49 (s, 9H), 1.37 (d, J=6.8Hz, 6H); MS m/z: 307 (M+1).

5.2.p N⁵-(2-Methoxyethyl)-N⁵-methylpyridin-2,5-yldiamine

MS m/z: 182 (M+1).

5.2.q 5-(4-Methoxypiperidin-1-yl)pyridin-2-ylamine

MS m/z: 208 (M+1).

Example 6

Preparation of 8

6.1 Ullmann Cross-Coupling

To a solution of 24.6 mmol of 9 and 27.3 mmol of 7 in 50 mL of1,4-dioxane was added 4.92 mmol of copper (I) iodide followed by theaddition of 49.2 mmol of K₃PO₄ and 4.92 mmol oftrans-cyclohexanediamine, then the resulting mixture was stirred at 100°C. for 12 h. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was diluted with CHCl₃, poured intowater, and insoluble material was removed by celite filtration. Thefiltrate was extracted with CHCl₃, dried over MgSO₄ and concentrated invacuo. The crude product was purified by column chromatography to give7.87 mmol of nitro derivative.

A solution of 7.66 mmol of nitro derivative and 0.5 g of Pd/C (10%) in150 mL of methanol was stirred overnight under H₂ (1 atm). Afterfiltering through celite, the solution was concentrated under reducedpressure to give 4.75 mmol of 8.

6.2 Results

Analytical data for exemplary compound of structure 8 are providedbelow.

6.2.a 4-(6-Aminopyridin-3-yl)-1-benzyl-1,4-diazepan-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (d, J=2.4 Hz, 1H), 7.17 (dd, J,=8.8 Hz,J₂=2.4 Hz, 1H), 7.30-7.36 (m, 5H), 6.40 (d, J=8.8 Hz, 1H), 5.90 (br s,2H), 3.66-3.72 (m, 2H), 3.59 (br s, 2H), 2.59-2.71 (m, 6H); MS m/z: 327(M+1).

Example 7

Preparation of 12

7.1 Halogenation

To a solution of 30.7 mmol of 11 and 5 mL of bromine in 48 mL ofhydrobromic acid (48%) at 0° C. was added 24 mL (25 M) of aqueous NaNO₂.The mixture was stirred for 1 h at rt before it was neutralized by 145mL of 3M NaOH. The aqueous solution was extracted with ethyl acetate,and the organic phase was washed with saturated NaCl, dried over MgSO₄,and concentrated under a reduced pressure. The crude product waspurified by column chromatography to give 24.6 mmol of 12.

7.2 Results

Analytical data for exemplary compounds of structure 12 are providedbelow.

7.2.a 2-Bromo-5-chloro-pyridine

¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=2.8 Hz, 1H), 7.89 (dd, J₁=8.5 Hz,J₂=2.7 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H); MS m/z: 192 (M+1).

7.2.b 2-Bromo-5-(4-fluoro-phenyl)-pyridine

¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (d, J=2.4 Hz, 1H), 8.03 (dd, J₁=8.3 Hz,J₂=2.6 Hz, 1H), 7.80-7.70 (m, 3H), 7.34 (d, J=6.6 Hz, 1H), 7.32 (d,J=6.8 Hz, 1H); MS m/z: 252(M+1).

Example 8

Preparation of 14

8.1 Stannylation

To a solution of 17.4 mmol of 13 in 60 mL of dry THF at −78° C. under N₂was added 19.2 mmol of n-BuLi (2.5 M in hexane), and the resulting brownsolution was stirred for 30 min before 20.9 mmol of Bu₃SnCl was added.The reaction mixture was allowed to warm to room temperature overnight.After the reaction was quenched with saturated NH₄Cl and the mixture wasextracted with ethyl acetate, the combined organic phase was washed withsaturated NaCl, dried over MgSO₄, and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel to give 10.5 mmol of 14.

8.2 Results

Analytical data for exemplary compounds of structure 14 are providedbelow.

8.2.a 4-Methyl-2-tributylstannanyl-pyridine

¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J=5.0 Hz, 1H), 7.21 (s, 1H), 6.93 (d,J=4.7 Hz, 1H), 2.29 (s, 3H), 1.61-1.47 (m, 6H), 1.39-1.29 (m, 6H),1.16-1.08 (m, 6H), 0.87 (t, J=7.3 Hz, 9H); MS m/z: 384 (M+1).

8.2.b 2-Methoxy-6-tributylstannanyl-pyridine

¹H NMR (300 MHz, CDCl₃) δ 7.39 (dd, J₁=8.3 Hz, J₂=6.9 Hz, 1H), 6.98 (d,J=6.1 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 1.62-1.53 (m, 6H),1.38-1.27 (m, 6H), 1.12-1.05 (m, 6H), 0.89 (t, J=5.9 Hz, 9H); MS m/z:400 (M+1).

8.2.c 5-Methyl-2-tributylstannanyl-pyridine

¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 7.30-7.24 (m, 2H), 2.25 (s, 3H),1.58-1.44 (m, 6H), 1.36-1.25 (m, 6H), 1.11-1.04 (m, 6H), 0.86 (t, J=7.1Hz, 9H); MS m/z: 384 (M+1).

8.2.d 4-Pyrrolidin-1-yl-2-tributylstannanyl-pyridine

¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (d, J=4.5 Hz, 1H), 6.68-6.64 (m, 1H),6.59 (d, J=2.4 Hz, 1H), 3.41 to 3.39 (m, 4H), 1.97 (bs, 4H), 1.58-1.41(m, 6H), 1.38-1.22 (m, 6H), 1.20-1.00 (m, 6H), 0.83 (t, J=7.3 Hz, 9H);MS m/z: 439 (M+1).

Example 9

Preparation of 16

9.1 General Method: Stille Cross-Coupling

A mixture of 0.3 mmol of 15, 0.36 mmol of 14, and 0.015 mmol ofPd(PPh₃)₄ in 4 mL of dry toluene was stirred for 2 days at 70° C. underN₂. The reaction was quenched with 10 mL of saturated NH₄Cl. After themixture was extracted with EtOAc, the organic phase was washed withsaturated NaCl, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel to give 0.063 mmol of 16.

9.2 Results

Analytical data for an exemplary compound of structure 16 is providedbelow.

9.2.a 2-Chloro-4-pyridin-2-yl-pyrimidine

¹H NMR (300 MHz, DMSO-d₆) δ 8.79 (d, J=5.0 Hz, 1H), 8.73 (d, J=3.8 Hz,1H), 8.47 (d, J=8.0 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.03-7.97 (m, 1H),7.58-7.53 (m, 1H); MS m/z: 192 (M+1).

Example 10

Preparation of 16

10.1 General Method: Nucleophilic Addition and Oxidation

To a solution of 127 mmol of 14 in 400 mL of dry THF at −78° C. wasadded 139 mmol of n-butyllithium (2.5 M in hexane) and the solution wasstirred for 30 min before 139 mmol of 17 in 100 mL of dry THF was addedover a period of 10 min. The resulting mixture was allowed to warm toroom temperature with stirring overnight. The reaction was quenched with10 mL of acetic acid. To the acidic mixture was added 139 mmol of DDQand the resulting mixture was stirred for 2 days at room temperaturebefore it was quenched with saturated NaHCO₃. After the mixture wasextracted with ethyl acetate, the organic phase was washed withsaturated NaCl, dried over MgSO₄, and concentrated in vacuo to afford 62mmol of 16.

Example 11

Preparation of 18

11.1 General Method

To a solution of 1.34 mmol of 2 or 8 in 20 mL of anhydrous THF was added2.68 mmol of NaH (60% in mineral oil) and the solution was stirred for10 min before the addition of 1.34 mmol of 15. The resulting mixture wasstirred at reflux for 1 day under N₂ and the reaction was quenched withsaturated NH₄Cl. The reaction mixture was diluted with 100 mL of ethylacetate and the organic solution was washed with saturated NaCl, driedover MgSO₄, and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel to afford 0.48 mmol of 18.

11.2 Results

Analytical data for exemplary compounds of structure 18 are providedbelow.

11.2.a (2-Chloro-pyrimidin-4-yl)-pyridin-2-yl-amine

¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.32 (d, J=6.0 Hz, 2H), 7.83(d, J=5.5 Hz, 1H), 7.81-7.74 (m, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.07-7.02(m, 1H); MS m/z: 207 (M+1).

11.2.b (5-Chloro-pyridin-2-yl)-(2-chloro-pyrimidin-4-yl)-amine

¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.35 (d, J=5.8 Hz, 2H), 7.90(dd, J₁=2.8 Hz, J₂=8.9 Hz, 1H), 7.71 (d, J=5.7 Hz, 1H), 7.60 (d, J=9.1Hz, 1H); MS m/z: 241 (M+1).

Example 12

Preparation of 19

12.1 General Method: Nucleophilic Replacement

To a solution of 0.58 mmol of 2 or 8 in 20 mL of anhydrous THF was added1.05 mmol of NaH (60% in mineral oil) and the solution was stirred for10 min before the addition of 0.53 mmol of 16. The resulting mixture wasstirred at reflux for 16 h under N₂ and then the reaction was quenchedwith saturated NH₄Cl. The reaction mixture was diluted with 100 mL ofethyl acetate and the organic solution was washed with saturated NaCl,dried over MgSO₄, and concentrated in vacuo. The crude product waspurified by column chromatography on silica gel to afford a quantitativeyield of 19.

12.2 Results

Analytical data for exemplary compounds of structure 19 are providedbelow.

12.2.a (5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-pyridin-2-yl-amine

¹H NMR (300 MHz, DMSO-d₆) δ 10.75 (bs, 1H), 8.90 (d, J=5.2 Hz, 1H),8.59-8.48 (m, 3H), 8.40 (t, J=7.8 Hz, 1H), 8.26-8.12 (m, 2H), 7.90 (t,J=6.4 Hz, 1H), 7.44-7.39 (m, 1H), 4.12 (s, 3H); MS m/z: 280 (M+1).

12.2.b(5-Chloro-pyridin-2-yl)-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-amine.2HCl

¹H NMR (300 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.86 (d, J=4.7 Hz, 1H),8.52-8.32 (m, 4H), 8.26 (d, J=8.9 Hz, 1H), 8.06 (dd, J₃=8.9 Hz, J₂=2.5Hz, 1H), 7.92-7.87 (m, 1H), 4.09 (s, 3H); MS m/z: 314 (M+1).

12.2.c(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-pyrrolidin-1-yl-pyridin-2-yl)-amine.2HCl

¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (bs, 1H), 8.89 (d, J=5.0 Hz, 1H), 8.45(d, J=7.8 Hz, 1H), 8.35 (s, 2H), 7.97 (d, J=9.4 Hz, 1H), 7.91-7.86 (m,1H), 7.84 (d, J=3.0 Hz, 1H), 7.55 (dd, J₃=9.3 Hz, J₂=3.0 Hz, 1H), 4.11(s, 3H), 3.37-3.30 (m, 4H), 1.99 (t, J=6.4 Hz, 4H); MS m/z: 349 (M+1).

12.2.d[5-(3-Fluoro-phenyl)-pyridin-2-yl]-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-amine.2HCl

¹H NMR (300 MHz, DMSO-d₆) δ 10.55 (bs, 1H), 8.93-8.89 (m, 2H), 8.56 (d,J=7.9 Hz, 1H), 8.46-8.41 (m, 3H), 8.34 (d, J=8.7 Hz, 1H), 7.96-7.91 (m,1H), 7.71-7.63 (m, 2H), 7.59-7.51 (d, 1H), 7.30-7.22 (m, 1H), 4.12 (s,3H); MS m/z: 374 (M+1).

12.2.e1-[6-(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-ylamino)-pyridin-3-yl]-pyrrolidin-2-one.2HCl

¹H NMR (300 MHz, DMSO-d₆) δ 10.27 (bs, 1H), 8.86 (d, J=4.7 Hz, 1H), 8.73(d, J=2.7 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 8.40-8.30 (m, 4H), 7.88-7.83(m, 1H), 4.10 (s, 3H), 3.90 (t, J=7.0 Hz, 2H), 2.55-2.47 (m, 2H), 2.11(t, J=7.5 Hz, 2H); MS m/z: 363 (M+1).

12.2f(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine.3HCl

¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (bs, 1H), 8.88 (d, J=4.6 Hz, 1H), 8.38(d, J=7.8 Hz, 1H), 8.31-8.26 (m, 3H), 8.01 (d, J=9.0 Hz, 1H), 7.86-7.78(m, 2H), 4.10 (s, 3H), 3.94 (d, J=12.7 Hz, 2H), 3.50 (d, J=11.7 Hz, 2H),3.32-3.14 (m, 4H), 2.79 (d, J=4.5 Hz, 3H); MS m/z: 378 (M+1).

12.2.g(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(4-methyl-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-6′-yl)-amine.2HCl

¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (bs, 1H), 8.91 (d, J=4.9 Hz, 1H),8.58-8.44 (m, 3H), 8.43 (s, 1H), 8.25-8.19 (m, 2H), 8.00-7.94 (m, 1H),4.11 (s, 3H), 3.71 (d, J=11.8 Hz, 2H), 3.16 (bs, 2H), 1.78 (d, J=12.5Hz, 2H), 1.70-1.45 (m, 3H), 0.95 (d, J=6.1 Hz, 3H); MS m/z: 377 (M+1).

Example 13

Preparation of 20

13.1 Negishi Cross-Coupling

A mixture of 0.08 mmol of 18, 0.08 mmol of 14, and 0.015 mmol ofPd(PPh₃)₄ in 4 mL of dry THF was stirred at reflux for 2 days under N₂.The reaction was quenched with 10 mL of saturated NH₄Cl. After themixture was extracted with EtOAc, the organic phase was washed withsaturated NaCl, dried over MgSO₄, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel to give 0.03 mmol of20.

13.2 Results

Analytical data for exemplary compounds of structure 20 are providedbelow.

13.2.a Pyridin-2-yl-(4-pyridin-2-yl-pyrimidin-2-yl)-amine

¹H NMR (300 MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.74 (d, J=3.5 Hz, 1H), 8.69(d, J=5.1 Hz, 1H), 8.42 (d, J=7.8 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.30(d, J=3.6 Hz, 1H), 8.04 (t, J=7.8 Hz, 1H), 7.81 (d, J=4.8 Hz, 2H),7.59-7.54 (m, 1H), 7.03-6.98 (m, 1H); MS m/z: 250(M+1).

13.2.b (5-Chloro-pyridin-2-yl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine

¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.76-8.69 (m, 2H), 8.43-8.32(m, 2H), 8.03 (dd, J₁=7.8 Hz, J₂=6.0 Hz, 1H), 7.90 (dd, J₁=8.9 Hz,J₂=2.5 Hz, 1H), 7.86-7.82 (m, 1H), 7.61-7.54 (m, 2H); MS m/z: 284 (M+1).

13.2.c (5-Phenyl-pyridin-2-yl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine

¹H NMR (300 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.76-8.71 (m, 2H), 8.64 (d,J=2.5 Hz, 1H), 8.45 (d, J=8.3 Hz, 2H), 8.14 (dd, J₁=2.4 Hz, J₂=8.7 Hz,1H), 8.04 (dt, J₁=1.8 Hz, J₂=7.8 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.71(d, J=7.3 Hz, 2H), 7.60-7.55 (m, 1H), 7.50-7.44 (m, 2H), 7.37 (d, J=7.3Hz, 1H); MS m/z: 326 (M+1).

Example 14

Preparation of 23

14.1 General Method

A mixture of 20.0 mmol of the corresponding carboxylic acid of 22, 15 mLof SOCl₂, and 5 drops of DMF was stirred at 60° C. for 3 h. The reactionmixture was concentrated in vacuo. To a solution of the crude 22 in 50mL of THF was added 20 mmol of 21 and 60 mmol of Et₃N and stirred atroom temperature for 2 h. The reaction mixture was concentrated and theresidue was diluted with water and AcOEt. The precipitates werecollected by filtration and washed with EtOH to give 1.1 mmol of 23.

Example 15

Preparation of 24

15.1 General Method

To a solution of 6.9 mmol of 23 in 20 mL of THF and 20 mL of t-BuOH wasadded 15 mmol of tBuOK and stirred at 80° C. for 2 h. The reactionmixture was quenched with 3 g of NH₄Cl and extracted with AcOEt. Theorganic phase was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was washed with AcOEt-n-hexane (1:2) to give 6.1mmol of 24.

Example 16

Preparation of 25

16.1 General Method

A mixture of 5.5 mmol of 24 in 15 mL of POCl₃ was stirred at 120° C. for1 h. reaction mixture was concentrated in vacuo and diluted with AcOEtand H₂O, and quenched with K₂CO₃. The precipitates were collected byfiltration to give 4.7 mmol of 25.

16.2 Results

Analytical data for exemplary compound of structure 25 is providedbelow.

16.2.a 4-Chloro-2-pyridin-2-ylquinazoline

¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=4.9 Hz, 1H), 8.50 (d, J=7.8 Hz,1H), 8.20 (dd, J₁=7.8 Hz, J₂=1.0 Hz, 1H), 8.11 (dt, J₃=7.8 Hz, J₂=1.5Hz, 1H), 7.83-7.92 (m, 2H), 7.68-7.71 (m, 1H), 7.57-7.61 (m, 1H); MSm/z: 243 (M+1).

Example 17

Preparation of 26

17.1 General Method

To a solution of 1.66 mmol of 25 in 15 mL of DMF was added 5 mmol of 60%NaH in oil at room temperature and 1.66 mmol of 2 or 8, and theresulting mixture was stirred at 60° C. for 4 h. The reaction mixturewas concentrated in vacuo and the residue was diluted with water andAcOEt. The mixture was extracted with AcOEt and the organic phase wasextracted with diluted HCl. Aqueous phase was made alkaline with K₂CO₃and extracted with AcOEt, and then organic phase was washed with brine,dried over MgSO₄, and concentrated. The residue was purified by columnchromatography on silica gel to give 0.94 mmol of ca. 1:1 tautomericmixture of 26.

17.2 General Method

Analytical data for exemplary compound of structure 26 is providedbelow.

17.2.a N,2-dipyridin-2-ylquinazolin-4-amine andN-[(4Z)-2-pyridin-2-ylquinazolin-4(3H)-ylidene]pyridin-2-amine (ca. 1:1tautomeric mixture)

¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 0.5H), 8.72-8.86 (m, 2H),8.42-8.57 (m, 2.5H), 8.08 (dt, J₁=7.8 Hz, J₂=2.0 Hz, 0.5H), 7.47-7.98(m, 6H), 7.32 (d, J=8.3 Hz, 0.5H), 7.11-7.17 (m, 1H); MS m/z: 300 (M+1).

Example 18

Preparation of 29

18.1 General Method

A mixture of 3.0 mmol of 27, 3.0 mmol of 14, and 0.09 mmol of Pd(PPh₃)₄in 20 mL of toluene was stirred at 100° C. for 20 h. The reactionmixture was diluted with AcOEt and H₂O, filtrated through celite, andthen extracted with AcOEt. The organic phase was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give 0.46 mmol of 28.

18.2 Results

Analytical data for exemplary compound of structure 28 is providedbelow.

18.2.a 2-Chloro-4-pyridin-2-ylquinazoline

¹H NMR (300 MHz, CDCl₃) δ 8.95-8.99 (m, 1H), 8.83-8.86 (m, 1H), 8.27(dt, J₁=7.9 Hz, J₂=0.9 Hz, 1H), 7.92-8.07 (m, 3H), 7.65-7.71 (m, 1H),7.49-7.54 (m, 1H); MS m/z: 243 (M+1).

18.3 General Method

To a solution of 1.66 mmol of 28 in 15 mL of DMF was added 5 mmol of 60%NaH in oil at room temperature and 1.66 mmol of 2 or 8, and theresulting mixture was stirred at 60° C. for 4 h. The reaction mixturewas concentrated in vacuo and the residue was diluted with water andAcOEt. The mixture was extracted with AcOEt and the organic phase wasextracted with diluted HCl. Aqueous phase was made alkaline with K₂CO₃and extracted with AcOEt, and then organic phase was washed with brine,dried over MgSO₄, and concentrated. The residue was purified by columnchromatography on silica gel to give 0.90 mmol of 29.

18.4 Results

Analytical data for exemplary compound of structure 29 is providedbelow.

18.4.a N,4-Dipyridin-2-ylquinazolin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.64(d, J=7.8 Hz, 1H), 8.60 (d, J=8.3 Hz, 1H), 8.34 (d, J=4.9 Hz, 1H), 8.21(d, J=7.8 Hz, 1H), 8.11 (dt, J₁=7.4 Hz, J₂=1.5 Hz, 1H), 7.82-7.90 (m,3H), 7.64-7.67 (m, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.02-7.06 (m, 1H); MSm/z: 300 (M+1).

Example 19

Preparation of the metal complex 30

19.1 Synthesis

0.1 mL of 1.0 M FeClO₄ in ether is added to a solution of 0.2 mmol of 20in EtOH at 60° C. A white precipitate forms immediately. To this mixtureis added 0.06 mL of triethyl amine and the resulting mixture is stirredfor 20 min. After the mixture is cooled to rt, the white precipitate isfiltered to yield 30.

Example 20

20.1 Assay for Compound Activity Towards hSK Channels

Cells expressing small conductance, calcium activated potassiumchannels, such as SK-like channels were loaded with ⁸⁶Rb⁺ by culture inmedia containing ⁸⁶RbCl. Following loading, the culture media wasremoved and the cells were washed in EBSS to remove residual traces of⁸⁶Rb⁺. Cells were preincubated with the drug (0.01 to 30 μM in EBSS) andthen ⁸⁶Rb⁺ efflux was stimulated by exposing cells to EBSS solutionsupplemented with a calcium ionophore, such as ionomycin, in thecontinued presence of the drug. After a suitable efflux period, theEBSS/ionophore solution was removed from the cells and the ⁸⁶Rb⁺ contentwas determined by Cherenkov counting (Wallac Trilux). Cells were thenlysed with a SDS solution and the ⁸⁶Rb⁺ content of the lysate wasdetermined. Percent ⁸⁶Rb⁺ efflux was calculated according to thefollowing equation:(⁸⁶ Rb ⁺ content in EBSS/(⁸⁶ Rb ⁺ content in EBSS+ ⁸⁶ Rb ⁺ content ofthe lysate))×10020.2 Results

Compounds tested in this assay, along with their hSK2 inhibitoryactivity, are provided in Table 1. TABLE 1 hSK2 Inhibitory Compound NameActivity (4-Methyl-pyridin-2-yl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine++++ N²-(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-pyridine-2,5-diamine++++(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-pyrrolidin-1-yl-pyridin-2-yl)-++++ amine1-[6-(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-ylamino)-pyridin-3-yl]-pyrrolidin-++++ 2-one(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-thiophen-2-yl-pyridin-2-yl)-++++ amine(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(4-methyl-3,4,5,6-tetrahydro-2H-++++ [1,3′]bipyridinyl-6′-yl)-amine(5-Methoxy-pyridin-2-yl)-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-amine++++(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-thiophen-3-yl-pyridin-2-yl)-++++ amine Pyridin-2-yl-(4-pyridin-2-yl-pyrimidin-2-yl)-amine ++++(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(4-methyl-pyridin-2-yl)-amine++++ (5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-pyridin-2-yl-amine +++(5-Chloro-pyridin-2-yl)-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-amine+++ (5-Chloro-pyridin-2-yl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amineN²-(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-N5,N5-dimethyl-pyridine-2,5-+++ diamine(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-phenyl-pyridin-2-yl)-amine+++ (5-Phenyl-pyridin-2-yl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine +++(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-[5-(4-methyl-piperazin-1-yl)-+++ pyridin-2-yl]-amine(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-[5-(5-methyl-furan-2-yl)-pyridin-2-+++ yl]-amine[5-(3-Fluoro-phenyl)-pyridin-2-yl]-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-+++ amine(5-Fluoro-pyridin-2-yl)-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-amine+++ Pyridin-2-yl-(2-pyridin-2-yl-quinazolin-4-yl)-amine +++4-Chloro-2,6-di-pyridin-2-yl-pyrimidine ++[2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-pyridin-2-yl-amine ++(5-Chloro-pyridin-2-yl)-(2-pyridin-2-yl-pyrimidin-4-yl)-amine ++[4-(6-methyl-pyridin-2-yl)-pyrimidin-2-yl]-pyridin-2-yl-amine ++(6-methyl-2-pyridin-2-yl-pyrimidin-4-yl)-pyridin-2-yl-amine +(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-nitro-pyridin-2-yl)-amine +(4-Pyridin-2-yl-pyrimidin-2-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine +N-(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-N′-pyridin-2-yl-hydrazine +(5-Bromo-pyridin-2-yl)-(5-methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-amine +Methyl-pyridin-2-yl-(4-pyridin-2-yl-pyrimidin-2-yl)-amine +Pyridin-2-yl-(4-pyridin-2-yl-quinazolin-2-yl)-amine +(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)- +amine(5-Chloro-6-methyl-2-pyridin-2-yl-pyrimidin-4-yl)-(5-trifluoromethyl-pyridin-2- +yl)-amine (2,6-Di-pyridin-2-yl-pyrimidin-4-yl)-pyridin-2-yl-amine +(2,6-Di-pyridin-2-yl-pyrimidin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine+Key:+ indicates 30 μM > IC50 > 5.0 μM;++ indicates 5.0 μM > IC50 > 1.0 μM;+++ indicates 1.0 μM > IC50 > 0.1 μM;++++ indicates 0.1 μM > IC50 > 0.0 μM.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound having a structure according to Formula I:

wherein A and B are independently substituted or unsubstituted 5- or6-membered heterocycloalkyl, or substituted or unsubstituted 5- or6-membered heteroaryl,

W² is —CH═, —NH—, —N═, or —O—;

Z² is —CH═, —NH—, —N═, or —O—; X is a bond, —CH₂—, or —W—; Y is a bond,—CH═N—NH—, —NH—CH₂—, or —NR⁵—; s and t are independently integers from 1to 4; k is an integer from 1 to 2; R¹, R², and R³ are independently H,—OH, —NO₂, —SO₂NH₂, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstituted3- to 7-membered cycloalkyl, substituted or unsubstituted 5- to7-membered heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or —NR⁷R⁸, wherein R⁷ and R⁸are independently H, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstituted5- to 7-membered cycloalkyl, substituted or unsubstituted 5- to7-membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, wherein R⁷ and R⁸ areoptionally joined together with the nitrogen to which they are attachedto form a substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, or substituted or unsubstituted heteroaryl; and R⁴ andR⁵ are independently H, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted 3- to7-membered cycloalkyl, substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; wherein if s is greater than one, then each R¹is optionally different; wherein if k is two, then each R² is optionallydifferent; wherein if t is greater than one, then each R³ is optionallydifferent; wherein two R¹ groups are optionally joined together with theatoms to which they are attached to form a substituted or unsubstitutedring; wherein two R² groups are optionally joined together with theatoms to which they are attached to form a substituted or unsubstitutedring; and wherein two R³ groups are optionally joined together with theatoms to which they are attached to form a substituted or unsubstitutedring.
 2. The compound of claim 1, wherein A is substituted orunsubstituted pyridinyl.
 3. The compound of claim 1, wherein B issubstituted or unsubstituted pyridinyl.
 4. The compound of claim 1,wherein R¹, R², and R³ are independently H, —NH₂, —NO₂, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.
 5. The compound of claim 4, wherein R¹ is H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, or substituted or unsubstituted aryl; R² is H, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, or substituted or unsubstituted aryl; R³ is H, —NH₂,—NO₂, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.
 6. The compound of claim 5,wherein R¹ is H, methyl, —NH₂, or unsubstituted phenyl; R² is H, Cl,methyl, —OCH₃, or unsubstituted pyridinyl; and R³ is H, —NH₂, —NO₂, Cl,Br, F, methyl, phenyl, fluorophenyl, —CF₃, —OCH₃, dimethylamino,unsubstituted piperidine, p-methyl morpholino, unsubstitutedpyrrolidinonyl, unsubstituted 2-thiophenyl, unsubstituted 3-thiophenyl,unsubstituted furanyl, or n-methyl piperizinyl.
 7. The compound of claim2, wherein X is a bond, k is 2, and R² is H or —OCH₃.
 8. The compound ofclaim 7, wherein Y is —NH—, t is 1, and B is

wherein R³ is H, —NH₂, —NO₂, halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted 3- to 7-membered cycloalkyl, substituted or unsubstituted5- to 7-membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.
 9. The compound of claim 8,wherein R³ is Cl or —NR⁷R⁸, wherein R⁷ and R⁸ are independently H,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted 5- to 7-memberedcycloalkyl, substituted or unsubstituted 5- to 7-memberedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, wherein R⁷ and R⁸ are optionally joinedtogether with the nitrogen to which they are attached to form asubstituted or unsubstituted 5- to 7-membered heterocycloalkyl, orsubstituted or unsubstituted heteroaryl.
 10. The compound of claim 9,wherein R³ is Cl, —NH₂, —N(CH₃)₂,


11. The compound of claim 7, wherein Y is —NH— and B is


12. The compound of claim 3, wherein Y is a bond, k is 1 and R² is H.13. The compound of claim 12, wherein X is —NH— and A is

wherein s is an integer from 1 to 4; and R¹ is H, halogen, —NH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted 5- to 7-membered cycloalkyl,substituted or unsubstituted 5- to 7-membered heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.
 14. The compound of claim 13, wherein A is


15. A metal complex, comprising a polyvalent metal ion and a polydentatecomponent of a metal ion chelator, wherein said polydentate component isa compound according to claim
 1. 16. The complex of claim 15, whereinsaid polyvalent metal ion is selected from iron, zinc, copper, cobalt,manganese, and nickel.
 17. A method of decreasing ion flow throughpotassium ion channels in a cell, said method comprising contacting saidcell with a potassium ion channel-modulating amount of the compound ofclaim
 1. 18. The method according to claim 17, wherein said potassiumion channel comprises at least one SK subunit.
 19. A method of treatinga disease through modulation of a potassium ion channel, said methodcomprising administering to a subject in need of such treatment, aneffective amount of the compound of claim
 1. 20. The method according toclaim 19, wherein said disorder or condition is selected from central orperipheral nervous system disorders, gastroesophogeal reflux disorder,gastrointestinal hypomotility disorders, irritable bowel syndrome,secretory diarrhea, asthma, cystic fibrosis, chronic obstructivepulmonary disease, rhinorrhea, convulsions, vascular spasms, coronaryartery spasms, renal disorders, polycystic kidney disease, bladderspasms, urinary incontinence, bladder outflow obstruction, ischemia,cerebral ischemia, ischemic heart disease, angina pectoris, coronaryheart disease, Reynaud's disease, intermittent claudication, Sjorgren'ssyndrome, arrhythmia, hypertension, myotonic muscle dystrophia,xerostomi, diabetes type II, hyperinsulinemia, premature labor,baldness, cancer, and immune suppression.
 21. The method according toclaim 20, wherein said central or peripheral nervous system disordercomprises migraine, ataxia, Parkinson's disease, bipolar disorders,trigeminal neuralgia, spasticity, mood disorders, brain tumors,psychotic disorders, myokymia, seizures, epilepsy, hearing and visionloss, psychosis, anxiety, depression, dementia, memory and attentiondeficits, Alzheimer's disease, age-related memory loss, learningdeficiencies, anxiety, traumatic brain injury, dysmenorrhea, narcolepsyand motor neuron diseases.
 22. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of the compound ofclaim 1.